Many materials useful in the treatment or diagnosis of disease are not soluble in water or other water-based solvent systems, which presents difficulties when attempting to administer such materials to people or animals. As a result, many processes have been designed and a great deal of research has been carried out to try and solve this insolubility problem and prepare these materials in a form in which they may be readily administered to and utilized by biological systems. For example, mechanically grinding or milling the materials has been attempted, as has chemically altering the materials with hydrophilic derivatives and thus increase the solubility of the materials. These methods have met with limited success and have often, particularly in the case of derivatization processes, proven costly. Moreover, derivatization of materials can introduce questions as to efficacy of the products due to the chemical alterations necessary to improve solubility.
It has been generally recognized that a suspension of nanoscale (i.e., less than 100 nm in size) materials is generally equivalent to a solution of the same materials when considered for medical applications such as the treatment or diagnosis of disease. As such, one approach to solving the insolubility problem of many biologically active materials has been directed toward the development of technologies that can produce suspensions of nanoscale materials.
Supercritical fluid processing techniques have shown promise in the production of micron- and submicron-sized (less than 1 μm) particles of water-insoluble materials, and in particular in regard to drug particles. For example, U.S. Pat. No. 6,576,264 to Henriksen, et al., and U.S. Pat. No. 6,177,103 to Pace, et al. describe processes that can generate submicron particles of biologically useful materials through the use of supercritical or compressed fluid processing techniques. Unfortunately, neither of these patented processes solves the insolubility problem of the materials, as both patents disclose processes that form particle suspensions including primarily or at least a substantial portion of drug particles over 100 nm in size. Suspensions that include a large percentage of particles larger than 100 nm in size are disadvantageous for medical applications due to, for instance, difficulties with intravenous delivery, slower dissolution rate (and thus slower system absorption), increased toxicity, lower intracellular uptake, shorter retention in tumor tissue, increased MPS (mononuclear phagocytic system) uptake, shorter circulating capacity in the blood, and lower stability against enzymatic degradation (especially for protein, peptide, and nucleic acid drugs). Drug particles greater than 100 nm in size can also be too large to penetrate into tissues through fine capillaries such as the liver sinusoidal.
In addition, these patents utilize phospholipids and surfactant materials during the disclosed processes and form micelles of these materials in the product suspension. As such, the aqueous suspensions as formed are believed to include empty micelles as well as drug particles within or in some physical combination with the micelle-forming materials. As such, the purity of the formed suspensions can be less than optimal. Moreover, the presence of the micelle-forming materials in the products could also interfere with the efficacy of the drugs.
What is needed in the art are improved methods for forming stable suspensions of nanoscale particles of biologically useful materials. In particular, what is needed in the art are methods for forming high purity, stable suspensions of nanoscale particles of biologically active materials with a very small size distribution among the particles held in the suspension.